Barbitlfric acid derivatives



Patented Jan. 16, 1940 uN Eo stares BARBITURIC ACID DERIVATIVES Walter H. Hartung,.Baltimore, Ma, and Frank s.

Crossley, I Philadelphi a, Pa., assignors, to Sharp & Dohme, Incorporated, Philadelphia, Pa, a I corporation of Maryland I No Drawing. Application October 15, 1936,

Serial No. 105,827

This invention relates toqnewderivatives of barbituric acid. It relates more particularly to new primary Aralkenyl barbituric acids in .the form of free acids or salts, and to new processes for their production. These new compounds are indicated to have valuable hypnotic and anaesthetic properties, with relatively low toxicity.

The compoundsproduced in accordance with this invention include various barbituric acid derivatives in which the two hydrogens attached to the methylene carbon are replaced, one by a primary nl-alkenyl group, and the other by an alkyl group, an aralkyl group, an aryl group, a cyclohydrocarbon group, such as the cyclohexyl or cyclopentyl group, or other hydrocarbon or substituted hydrocarbon residue. The compounds may be represented by the graphic formula.

' R CO NH,

. o o=o I .,I 'R/to tfl I I in which R represents a primary A1-alkenyl group, which may have more than one; double bond, and, R1 represents another hydrocarbon or substituted hydrocarbon group, which may be saturated or unsaturated, and which may have an open or closed chain. These compounds have a nitrogen-linked hydrogen capable, of being replaced to form salts; and salts of the acids may be readily prepared by replacing this hydrogenby a monovalent metal, suchas sodium or potassium, or an equivalent of a polyvalent metal, such as calcium or magnesium, or a nitrogen base, such as ammonia, alkylamines or dialkylamines, such as ethylamin-e or diethylamine, alkynolamines, such as diethanolamine, ephedrine, cocaine, phenylpropanolamine, or the like.

These compounds maybe produced by various methods. One advantageous method consists in condensing a di-ester of the corresponding malonic acid withurea, in the presence of sodium ethoxide at ordinary pressure. Another advantageous method consists in condensing the corresponding cyanoacetic ester with urea, in the presence of sodium ethoxide or the like, and subjecting the resulting imino derivative to hydrolysis to remove the imino group. The barbituric acids may, in some cases, be produced by the condensation of the corresponding cyanoacetic ester with 'thiourea, with hydrolysis of the resulting imino thiobarbituric acid with the removal of the imino group and the substitution I of an oxygen atom for .the sulfur atom. These methods will be illustrated in specific examples, with particular reference to the production of primary m-alkenyl alkyl derivatives, but the invention is not limited thereto.

Example 1.-Into a suitable reaction vessel, equipped with a stirrer, reflux condenser, and dropping funnel, are placed about 200 parts of anhydrous alcohol and 23 parts of sodium are dissolved therein- 30 parts of urea and 81 parts of ethyl n nl-butenyl inalonic ester are then added and the mixture is refluxed for about 8 to 12 hours, with constant stirring, after which "the alcohol is distilled ofi at reduced, pressure. The residue-is taken up inwater, and the neutral products which it contains (amides or unused ester) are removed by extraction with ether. The ether is then'distilled from the aqueous layer under reduced pressure, and the aqueous solution is cooled in an ice bath and slowly acidified with about l25 l55"parts of concentrated hydrochloric acid. ti-ethyl 5-n' Arbutenyl barbituric acid precipitates. This product is purifiedby recrystallization from an appropriate solvent, such as water oraq'ue'ous alcohol. It melts at 108-109" 1 i I q If, in the process'described in the preceding example, the corresponding cyanoacetic ester is used, the acidification precipitates 5-ethyl 5-n A1-butenyl4-imino barbituric acid. "This imino derivative may be converted into the corresponding barbituric acid by hydrolyzing-witlr boiling mineral acid solution, e. g., 20% hydrochloric or sulfuric acid. I I

Example 2.81 parts of ethyl m-isobutenyl malonic ester and 30 parts of urea are reacted in a solution of 23 parts of sodium in about 200 parts of absolute alcohol, as in Example 1. The 5-ethyl 5Ai-isobutenyl barbituric acid obtained has a melting point of 128-129" C. I

Example 3.84= parts of isopropyl n-m-butenyl malonic ester and 38 parts of ,ureaare reactedin a solution of 23 parts of sodium in about 200 parts of absolute alcohol, as in Example 1. The 5-isopropyl 5-n m-bu'tenyl barbituric acid obtained has a melting point of 108-109 C.

Example 4.-55 parts of methyl n-m-butenyl malonic ester and 30 parts of urea are reacted in a solution of 23 parts of sodium in about 200 parts of absolutealcohol, as in Example 1, with the production of 5-n1ethyl 5-n-A1-butenyl barbituric acid.

The primary m-alkenyl alkyl malonic esters used, in accordance with the present invention, for the production of corresponding 5-alky1 5- ni-alkenyl barbituric and thiobarbituric acids may be readily prepared from primary alkylidene malonic esters by the alkylation of such esters with an alkyl salt in the presence of a sodium alkoxide or the like. The primary A1- alkenyl alkyl cyanoacetic esters may be readily prepared by the condensation of the corresponding primary alkylid'ene cyanoacetic esters with an alkyl salt in the presence of a sodium alkoXlde or the like. Or both the alkyl Avalkenyl cyanoacetic esters and the malonic esters may be prepared by reacting an alkyl salt, such as an alkyl halide or sulfate, with an alkylidene malonic ester or cyanoacetic ester in an inert solvent in the presence of metallic sodium.

A wide range of primary Ar-alkenyl barbituric and thiobarbituric acids may be prepared by the.

process of the present invention. Included among the new primary A1-alkeny1 barbituric and thiobarbituric acids which may be prepared by the process of the foregoing examples are compounds in which the primary A1-alkenyl group may be one of the following:

Ai-n-propenyl Ai-butenyl (normal or iso) Ai-pentenyl (normal or iso) m-hexenyl (normal or iso) Ai-heptenyl (normal or iso) Ara-butadienyl A1, 7-1,3-dimethyl octadienyl (Ai-citronellenyl) phenyl-vinyl Ai-phenyl-propenyl and others, and in which the other bond of the methylene carbon may be attached to one of the following radicals:

Methyl Ethyl Propyl (normal or iso) Butyl (normal, iso or secondary) Allyl Crotyl Amyl (normal, iso or secondary) Hexyl (normal, iso 01' secondary) Heptyl (normal, iso or secondary) Cyclohexyl Cyclopentyl Phenyl-ethyl Benzyl Citronellyl Cinnamyl and others These primary Ar-alkenyl barbituric acids have a nitrogen-linked hydrogen replaceable by a metal or a nitrogen base, and hence it is possible to form salts of these acids. For example, the sodium salts, which are water soluble, may be conveniently prepared by reacting one of the free acids with an equivalent of sodium ethoxide in absolute alcohol. If the resulting salt is too soluble in alcohol to be readily separated it may be precipitated by the addition of ligroin or the like.

The term alkyl, as used in this specification and the appended claims is to be construed in its broader sense, as including saturated and unsaturated compounds, whether straight chain or branched chain, as well as aralkyl compounds; and the term alkenyl is also to be construed in its broader sense, to include compounds in which the alkenyl group is straight or branched chain, including compounds in which this group contains more than one double bond, as well as aralkenyl compounds.

We claim:

1. Primary 5-A1-alkenyl barbituric acids in which the A1-alkenyl group has at least three carbon atoms.

2. Primary 5-A1-alkenyl 5-alkyl barbituric acids in which the Ai-alkenyl group has at least three carbon atoms.

3. 5-ethyl 5-A1-n-butenyl barbituric acid.

4. Primary 5-A1-buteny1 barbituric acids.

5. Primary 5-A1-hepteny1 barbituric acids.

6. Primary 5-A1-n-butenyl barbituric acids.

'1. Primary 5-A1-alkenylv barbituric acids in which the alkenyl group has at least four carbon atoms.

8. Primary 5-A1-alkenyl 5-alkyl barbituric acids in which the alkenyl group has at least four carbon atoms.

WALTER H. HARTUNG. FRANK S. CROSSLEY.

CERTIFICATE OF CORRECTION. Patent No. 2,187,705. January 16, 1 11.0.

WALTER H; EARTUNG, ET AL.

It is hereby certified that error appears in the printed specification of the above numbered patent requiring correction as follows; Page 1, second column, line 8, and page 2, first column, lines LL and 6-7, strike out the words "and thiobarbituric"; and that the said Letters Patent should be readwith this correction therein that the same may conform to the record of the case in the Patent Office. 4

Signed and sealed this 12th day of March, A. D. l9L O.

Henry Van Arsdale, (Seal) Acting Commissioner of Patents. 

